Alzheimer disease (AD) is a complex phenotype influenced by the cumulative impact of many genetic elements. While environmental factors and age certainly contribute to phenotypic expression, we hypothesize that the underlying biological process of AD is driven by the burden of genetic variants influencing risk. Understanding how genetic burden causes disease can inform efforts to develop more effective AD therapeutics. Furthermore, the spectrum of known AD genetic risk variants implicates numerous cell types and thus knowing how variants impact biological networks and in which cell type is critical to directing therapeutic target design. In this proposal we leverage our collaborative and interdisciplinary AD research programs at the University of Washington and SAGE Bionetworks to create a cell-type specific systems biology program in AD. We hypothesize that non-coding variants confer AD risk through disruption of cellular pathways which can be identified by molecular phenotyping of AD patient brain tissue and assayed in vitro. Specifically, we focus on endosome biology given the link between endosome pathways and neural cell function and the known association with endosomal genetic variant risk and AD. Through the use of an endosome pathway specific polygenic risk score we can enrich our AD cohort for those more likely to manifest AD driven by endosomal dysfunction. We will employ single nuclei transcriptomics and functional studies in reprogrammed neural cells derived from the same cohort to investigate the impact of genetic risk in endosomal pathways on AD pathophysiology. We will 1) determine if a high endosome pathway polygenic risk score predicts endosome dysfunction in neurons and 2) determine how high endosome polygenic risk influences microglia function. Through development of these datasets, which will be available as open-source through SAGE Bionetworks, we can begin to identify the cell type specific transcriptomic changes in AD associated with endosomal variant load as well as the concomitant functional cell alterations using induced pluripotent stem cell derived neurons, microglia and transdifferentiated neurons. Our integrated molecular and cell biology phenotyping approach seeks to identify biological pathways by which aggregate endosomal genetic risk may contribute to AD pathogenesis and elucidate the cellular subtypes most directly impacted by endosomal dysfunction. Understanding candidate biological pathways and the cell types in which they are disrupted will provide valuable information for more effective therapeutic targeting in AD.